Evaluation of regional haemodynamics and alterations of vascular wall of the lower limbs in hypertensive subjects

This study was designed to analyse the relationship betweenarterial hypertension and changes in arterial blood flow andvascular wall damage of the lower limbs in hypertensive patientswith various degrees of hypertension. Six hundred and fifty-four hypertensive patients (421 malesand 233 females) aged 35 to 70 years and 88 healthy subjects(63 males and 25 females) aged 39 to 60 years were studied.Strain-gauge plethysmography of the lower limbs was used tocalculate arterial calf blood flow (RF), arterial calf bloodflow after post-ischaemic hyperaemia (PF), basal and minimalvascular resistances (BVR and MVR), time to reach peak flow(tPF), time until 50% reduction of peak flow (tT) and totalrecovery time (tT). In 108 (67 males and 41 females) of the hypertensive patients,a morphological study by echo-Doppler duplex scanning of thepopliteal artery was performed to measure medial-intimal thickeningand popliteal lumen diameter. Our results indicate that regional haemodynamics of the lowerlimbs worsened in hypertensives in comparison with control subjects.In addition, the change in peripheral haemodynamics was relatedto the degree of hypertension. Moreover, medial-intimal thickeningwas significantly (P<0.05) higher in severe hypertensivesthan mild hypertensives. Popliteal lumen diameter was significantly(P<0.05) lower in severe hypertensives than moderate andmild hypertensives. In all these subjects mean blood pressurewas correlated directly (r=0.31; P<0.001) with medial-intimalthickening and inversely (r= – 0.37; P<0.001) withpopliteal lumen diameter. Multiple regression analysis indicatedthat mean blood pressure, age and serum cholesterol were independentlycorrelated to medial-intimal thickening. This relationship wasnot influenced by the diabetic patients and smokers among thegroups. Our results indicate that hypertension impairs peripheral flowand encourages the development of medial-intimal thickening.     

Tumor-associated lymphocytes (TAL) are competent to produce higher levels of cytokines in neoplastic pleural and peritoneal effusions than those found in sera and are able to release into culture higher levels of IL-2 and IL-6 than those released by PBMC

This work was designed to study the proliferative response of tumor-associated lymphocytes (TAL) from neoplastic effusions against autologous tumor cells and the immunophenotype pattern of TAL from neoplastic effusions and that of PBMC of the same patients. We also compared the serum levels of the cytokines interleukin (IL) 1, 2 and 6, tumor necrosis factor- (TNF) and soluble IL-2 receptor (sIL-2R) with those present in neoplastic effusions of the same patients. Moreover, we examined the ability of TAL and peripheral blood mononuclear cells (PBMC) to produce and release the cytokines and sIL-2R and to express membrane CD25 following their stimulation with phytohemagglutinin (PHA) in vitro. Finally, we compared the cytokines/sIL-2R production and membrane CD25 expression by PHA-stimulated PBMC of the patients with neoplastic effusions with a series of 90 cancer patients without neoplastic effusions and 20 normal healthy subjects. Thirteen neoplastic pleural and eight peritoneal effusions were collected from 11 patients with primary lung cancer, 7 with primary epithelial ovarian cancer, 1 with breast cancer, 1 with pleural mesothelioma, and 1 with pancreatic cancer. The proliferative response of TAL from neoplastic effusions against autologous tumor cells was lower than the response to PHA, IL-2, and anti-CD3, but significant. The percentage distribution of CD3⁺ and CD8⁺ lymphocyte subpopulations was higher in peritoneal than in pleural effusions, while the CD16⁺ subset was higher in pleural than in peritoneal effusions. The percentage distribution of CD16⁺ was significantly lower in pleural effusions than in PBMC of patients with pleural effusions. The CD39 antigen was higher on TAL from peritoneal effusions than on PBMC of the same patients. The levels of IL-1 and sIL-2R in peritoneal effusions did not differ from those measured in the sera of the same patients, while the levels of IL-2, IL-6, and TNF were higher in the peritoneal effusions. The levels of IL-2, IL-6, TNF, and sIL-2R, but not IL-1, in pleural effusions were significantly higher than those found in the sera of the same patients. The amounts of IL-2 and IL-6 produced by TAL were generally higher than those released by PBMC. The secretion of cytokines IL-1, IL-2, and sIL2R by PHA-stimulated PBMC was lower, but IL-1 and IL-6 secretion was higher in cancer patients with neoplastic effusions than in either cancer patients without neoplastic effusions or normal subjects. The CD25 expression on PHA-stimulated PBMC derived from cancer patients with neoplastic effusions was in the same range as that of cancer patients without neoplastic effusions and normal subjects. These findings suggest that TAL may be able to produce cytokines and may be amenable to immune manipulation.Abbreviations FITC Fluorescein-isothiocyanate - IL Interleukin - mAb Monoclonal antibody - MHC Major histocompatibility complex - NK Natural killer - PBMC Peripheral blood mononuclear cells - PHA Phytohemagglutinin - TAL Tumor-associated lymphocytes - TIL Tumor-infiltrating lymphocytes - TNF Tumor necrosis factor- - sIL-2R Soluble interleukin-2 receptor     

Steps to optimize transscleral photocoagulation

Background: In transscleral photocoagulation, the desired effect is coagulation of parts of the ciliary body or of the peripheral retina. However, the application is often limited by the unwanted effect of coagulation of the sclera. to reduce this effect, the ratio of incident radiation flux to radiation flux transported through the sclera (and able to coagulate the target tissue) should be minimized by the incident beam characteristics.Methods: Monte Carlo simulations for the radiation transport problem of multiple scattering in the sclera were used to calculate the ratio of transported to incident radiation for different parameter settings of beam diameters, optical thicknesses of the sclera and beam angles. To verify the theoretical calculations, an simple optical device utilizing a bulb instead of a laser source was constructed and applied to enucleated porcine eyes.Results: The theoretical calculations showed that the ratio of incident to transported radiation flux can typically be decreased by a factor of three by increasing the beam radius from 0.35 mm (as used in state-of-the-art laser devices) to 2 mm. This was confirmed by the experiments. Coagulations of the ciliary body or of the peripheral retina were possible with power densities an order of magnitude below the values normally applied with laser sources.Conclusion: To improve transscleral photocoagulation, beam diameters should be increased.     

Ionic and haemodynamic changes influence the release of the excitatory amino acid glutamate in the posterior hypothalamus

The push-pull technique was used to investigate the release of the excitatory amino acid glutamate in the posterior hypothalamic area of the conscious rat. The hypothalamus was superfused through the pushpull cannula with artificial cerebrospinal fluid (CSF), and the superfusate was collected in time periods of 10 min when ionic conditions in the CSF were changed, or in short periods of 3 min when blood pressure changes were evoked. The mean glutamate release rate was 2.8 + 0.7 pmol/min. Depolarization by hypothalamic superfusion with CSF containing 50 mM K⁺ enhanced the release of glutamate in the presence of Ca²⁺. The K⁺-induced release was attenuated by 40% when the hypothalamus was superfused with Ca²⁺-free CSF. Replacement of Ca²⁺ by Mg²⁺ abolished the K⁺-induced release of glutamate. Hypovolaemia elicited by haemorrhage enhanced the release rate of glutamate. Similarly, a hypotension elicited by i.v. injection of chlorisondamine (3 mg/kg) led to a pronounced and permanent enhancement in glutamate release. The effects of hypovolaemia and chlorisondamine on glutamate release were abolished in aortic denervated rats, indicating that this response is due to a decrease of impulse generation in baroreceptors. A hypovolaemia elicited by blood infusion did not affect the release of glutamate. Similarly, a pronounced pressor response to phenylephrine (15 /kg per minute) infused intravenously for 9 min was ineffective.The results show that the K⁺-induced release of glutamate in the hypothalamus is dependent on the presence of Ca²⁺. The increase in glutamate release rate by hypovolaemia or chlorisondamine suggests that the glutamatergic neurons in the posterior hypothalamic area respond to unloading of aortic baroreceptors and possess a counteracting, hypertensive function.     

血瘀证目征与血瘀证诊断标准的比较研究

通过６种标准对７８１例患者的诊断研究,提示在诊断阳性率,敏感度,特异度,假阳性率假阴性率和总和积分值等方面,中国血瘀症诊断标准和国际血瘀证诊断标准最优,血瘀证目片和日本瘀血证诊断标准次之,国际瘀血诊断标准试行方案和中山氏瘀血压痛点更次之。各种标准各有其独特优点,应相互取长补短,同时,探讨了导致各种标准不足之处的原因,并提出合理建议。     

Laser Doppler velocimetry in retinal arteries of infants

The present study was conducted to assess the feasibility of laser Doppler velocimetry in young infants, as a prelude to ultimately undertaking such measurements in premature infants. A portable, unidirectional laser Doppler velocimeter was developed based on a Kowa RC-2 hand-held fundus camera. Six infants between 1 and 21 weeks of age were studied. Relative red blood cell velocity (f_max) at the centre of retinal arteries was measured over approximately 10 heart cycles. A pulsatility parameter (P=1–f_max.dia/f_max.sys), a summary index of vascular status, was determined from the average diastolic and systolic values of f_max. Velocity waveforms were obtained in four of the six infants. Arterial pulsatility for the group was 0.63±0.13. Precise non-invasive measurement of arterial red blood cell velocity waveforms in young infants was achieved. The high signal-to-noise ratio and temporal resolution of this data suggest that relative measurements of retinal blood flow may permit assessment of haemodynamic changes in premature infants.     

生脉散对小鼠多能造血干细胞（CFU－S）影响的实验研究

生脉散系著名古方,广泛用于多种疾病所致“气阴两虚”证。采用符合该证的实验性骨髓抑制及贫血小鼠,以脾集落法等项技术观察生脉散对小鼠血发生的影响。将对照组与实验组进行比较,结果显示：生脉散可刺激多能造血干细胞增殖（Ｐ＜０．０５）,骨髓有核细胞增生（Ｐ＜０．０５）,白细胞增生（Ｐ＜０．０１）,对Ｈｂ及红细胞作用不明显（Ｐ＞０．０５）．结合其他学者的工作,推测生脉散的“益气养阴”作用与影响血发生功能有关。     

Effect of moxonidine on urinary electrolyte excretion and renal haemodynamics in man

Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with nonadrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with ₂-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na⁺/H⁺ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (aged 25 ± 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA. MAP and PRA did not change with administration of placebo. Injection of moxonidine did not affect GFR and RVR; ERPF decreased slightly but not significantly. Acute administration of 0.2 mg i.v. moxonidine decreased blood pressure in healthy volunteers on standardized salt intake, but did not affect natriuresis, proximal tubular sodium reabsorption or glomerular filtration rate. The absence of an antinatriuretic response despite a decrease in blood pressure suggests a direct facilitation of natriuresis by moxonidine.     

Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the link model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid E_max PD model. For the 300 mg BID dose, PD parameters were: maximum effect (E_max), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC₅₀), 0.87 g·ml^–1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple E_max PD model. PD parameters obtained over the dose range were: E_max, 10.3 mmHg; Eo, 2.0 mmHg; and EC₅₀, 0.7 g·ml^–1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 g·ml^–1.     

Venous plasma levels of endothelin-1 are not altered immediately after nitroglycerin infusion in healthy subjects

Endothelin-1 and nitric oxide play an important regulatory role in the control of vascular smooth muscle tone. Nitroglycerin (NTG), a nitric oxide donating drug, may inhibit endothelin production. In this double-blind placebo-controlled crossover study, plasma levels of endothelin-1 were measured before and immediately (5–30 s) after 80 min infusion of NTG (glyceryl trinitrate) or saline in 12 healthy subjects. On two different days separated by at least 1 week, NTG in four different doses, 0.015, 0.25, 1.0, and 2.0 g·kg^–1·min^–1, or placebo (isotonic saline) was infused successively for 20 min each dose. During the infusion blood pressure and heart rate were measured. NTG infusion significantly decreased systolic blood pressure from 112.4 to 103.4 mmHg and pulse pressure from 39.3 to 29.5 mmHg. Heart rate increased from 62.7 to 73.1 beats·min^–1. No changes in endothelin-1 plasma levels were induced by NTG infusion (2.4 pg·ml^–1 before NTG vs. 2.7 pg·ml^–1 after NTG) and placebo infusion also did not affect plasma endothelin-1. It is concluded that venous plasma levels of endothelin-1 are not altered immediately after NTG infusion.